DNA Damage and Inflammation in Aging
Both stochastic DNA damage and chronic inflammation are characteristic of aging. DNA damage can contribute to inflammatory signaling via a range of mechanisms, but, as noted here, it is challenging in a system as complex as our cellular biochemistry to pick apart the relative importance of these mechanisms. It is nonetheless reasonable to think that some fraction of the unresolved inflammation of aging, disruptive to tissue function throughout the body, results from the increased amount of DNA damage in later life.
Persistent DNA lesions build up with aging triggering inflammation, the body's first line of immune defense strategy against foreign pathogens and irritants. Once established, DNA damage-driven inflammation takes on a momentum of its own, due to the amplification and feedback loops of the immune system leading to cellular malfunction, tissue degenerative changes, and metabolic complications.
There is much work to be done before we will be able to dissect the functional links between persistent DNA damage and inflammation in vivo. The use of progeroid murine models with tissue-specific defects in genome maintenance will allow us to further delineate the causal contribution of specific cell types to systemic inflammation with old age. In parallel, animal models with tagged DNA repair factors coupled to functional genomics and proteomics strategies may prove valuable for identifying new gene targets or protein partners that could link genome maintenance with innate immune signaling. It will also be essential to identify how an active DNA damage response originating from any alterations in the physicochemical structure of the DNA activates cytoplasmic stress responses and the release of proinflammatory factors in the tissue microenvironment.
Likewise, it will be vital to dissect the functional links between DNA damage-driven chronic inflammation and metabolic rewiring with old age. Finally, the recent development of novel therapeutic strategies indicates that, in the long run, it may be more valuable to invest in approaches targeting the DNA damage itself rather than suppressing downstream proinflammatory signals. Such strategies could open new, meaningful avenues towards the development of new rationalized therapeutic interventions against a wide range of adverse pathological outcomes during aging
I find this depressing.
3000 random errors that are different in every cell across the body is going to be hard to fix.
I'd say yes, it makes a lot of sense that our immune system, which was trained on our youthful, non mutated cells, struggles to differentiate harmful cells from healthy ones with all these spurious changes.
Depressing because how the heck could it ever be fixed?
Seems like we'd need to get very good at repairing and replacing progenitor cells while targeting and removing anything that is has a targetable change.
Anyone else have an idea on how this dilemma may ever get solved?
It should be quite doable, but tedious, for the more expendable cells. In principle one could sequence a person's genome several times, so as to generate a consensus sequence of what the person's un-mutated genome looks like. Then culture some stem cells, sequence their genome, and perform gene therapy to correct every way in which their genome differs from the consensus sequence. Use these cells to replace the patient's stem cells, and then over time telomere shortening will ensure that all cell lines not descended from these corrected stem cells will eventually die out. For non-expendable cells, like brain cells, things are much trickier - my best guess is that you'd have to engineer a way to transfer an entire nucleus to a cell (and get rid of the old one), while managing to transfer all the epigenetic settings over to the new nucleus (which *might* happen automatically if you do it only a very small number of cells at a time - the signalling from surrounding cells *might* be sufficient to tell the cell what it's supposed to be doing).
Maybe the first question to answer is how important are these DNA mutations to the overall dysfunction of the body. Any experiment ideas on how that might be answered?
@Arcanyn I think one trouble with the plan for fixing brain DNA errors could be that memories are stored in the epigenome, no? Not sure about that but somehow remember reading something about that.
However, maybe there is enough redundancy across neurons where you could randomly insert new neurons while you remove damaged ones in a very limited fashion. Sort of like add 0.5% and then removes 0.5% or even less and just keep doing that until you've replaced them all.
For the cells that undergo mitosis I've seen recently whereby cells which acquire a proliferation advantage start to take over as we age. something called chip can affect our blood cells. And I don't remember where but I remember seeing something about this also affects somatic cells.